Displaying publications 1 - 20 of 611 in total

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  1. Shahbuddin HMA, Hussin SA, W Isa WYH, Mamat AZ, Marzuki A, Yusof Z
    BMJ Case Rep, 2024 Mar 07;17(3).
    PMID: 38453227 DOI: 10.1136/bcr-2024-259675
    Diagnosing atrial myxoma in pregnancy is challenging because patients may present with non-specific symptoms that might be overlooked. The timing of non-obstetric operation usually depends on the nature of the disease, after careful consideration of feto-maternal safety, including the use of cardiopulmonary bypass and placental transfer of anaesthetic drug. A woman in her 30s at 18 weeks of pregnancy presented with recurring dizziness. She underwent successful myxoma excision at 20 weeks under general anaesthesia and cardiopulmonary bypass. The 6×5 cm myxoma was histologically confirmed as myxoma. Early detection of atrial myxoma in pregnancy is crucial, and a clinician has to consider the diagnosis of left atrial myxoma with mitral valve obstruction as a cause of severe dizziness. Optimal outcomes require multidisciplinary management. In this case, surgery during the second trimester of pregnancy enabled a full-term pregnancy with the patient's and foetal well-being and normal postprocedural echocardiography.
    Matched MeSH terms: Neoplasm Recurrence, Local/complications
  2. Chuah KH, Ramasami N, Mahendran HA, Shanmuganathan G, Koleth GG, Voon K, et al.
    J Gastroenterol Hepatol, 2024 Mar;39(3):431-445.
    PMID: 38087846 DOI: 10.1111/jgh.16403
    Disorders of esophagogastric junction (EGJ) outflow, including achalasia and EGJ outflow obstruction, are motility disorders characterized by inadequate relaxation of lower esophageal sphincter with or without impaired esophageal peristalsis. Current guidelines are technical and less practical in the Asia-Pacific region, and there are still massive challenges in timely diagnosis and managing these disorders effectively. Therefore, a Malaysian joint societies' task force has developed a consensus on disorders of EGJ outflow based on the latest evidence, while taking into consideration the practical relevance of local and regional context and resources. Twenty-one statements were established after a series of meetings and extensive review of literatures. The Delphi method was used in the consensus voting process. This consensus focuses on the definition, diagnostic investigations, the aims of treatment outcome, non-surgical or surgical treatment options, management of treatment failure or relapse, and the management of complications. This consensus advocates the use of high-resolution esophageal manometry for diagnosis of disorders of EGJ outflow. Myotomy, via either endoscopy or laparoscopy, is the preferred treatment option, while pneumatic dilatation can serve as a secondary option. Evaluation and management of complications including post-procedural reflux and cancer surveillance are recommended.
    Matched MeSH terms: Neoplasm Recurrence, Local/complications
  3. Commons RJ, Rajasekhar M, Edler P, Abreha T, Awab GR, Baird JK, et al.
    Lancet Infect Dis, 2024 Feb;24(2):172-183.
    PMID: 37748496 DOI: 10.1016/S1473-3099(23)00430-9
    BACKGROUND: Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy and tolerability of different primaquine dosing regimens to prevent P vivax recurrence.

    METHODS: For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, and if they included a treatment group with daily primaquine given over multiple days, where primaquine was commenced within 7 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine). We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. We assessed the effects of total dose and duration of primaquine regimens on the rate of first P vivax recurrence between day 7 and day 180 by Cox's proportional hazards regression (efficacy analysis). The effect of primaquine daily dose on gastrointestinal symptoms on days 5-7 was assessed by modified Poisson regression (tolerability analysis). The study was registered with PROSPERO, CRD42019154470.

    FINDINGS: Of 226 identified studies, 23 studies with patient-level data from 6879 patients from 16 countries were included in the efficacy analysis. At day 180, the risk of recurrence was 51·0% (95% CI 48·2-53·9) in 1470 patients treated without primaquine, 19·3% (16·9-21·9) in 2569 patients treated with a low total dose of primaquine (approximately 3·5 mg/kg), and 8·1% (7·0-9·4) in 2811 patients treated with a high total dose of primaquine (approximately 7 mg/kg), regardless of primaquine treatment duration. Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17-0·27; p<0·0001) and high-dose primaquine (0·10, 0·08-0·12; p<0·0001). High-dose primaquine had greater efficacy than low-dose primaquine in regions with high and low relapse periodicity (ie, the time from initial infection to vivax relapse). 16 studies with patient-level data from 5609 patients from ten countries were included in the tolerability analysis. Gastrointestinal symptoms on days 5-7 were reported by 4·0% (95% CI 0·0-8·7) of 893 patients treated without primaquine, 6·2% (0·5-12·0) of 737 patients treated with a low daily dose of primaquine (approximately 0·25 mg/kg per day), 5·9% (1·8-10·1) of 1123 patients treated with an intermediate daily dose (approximately 0·5 mg/kg per day) and 10·9% (5·7-16·1) of 1178 patients treated with a high daily dose (approximately 1 mg/kg per day). 20 of 23 studies included in the efficacy analysis and 15 of 16 in the tolerability analysis had a low or unclear risk of bias.

    INTERPRETATION: Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms.

    FUNDING: Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

    Matched MeSH terms: Recurrence
  4. Yong CM, Yehgambaram PAP, Lee SWH
    PLoS One, 2024;19(2):e0298130.
    PMID: 38300930 DOI: 10.1371/journal.pone.0298130
    INTRODUCTION: Ovarian cancer is one of the most common cancer among women in Malaysia. Patients with ovarian cancer are often diagnosed at an advanced stage. Despite initial response to surgery and chemotherapy, most patients will experience a relapse. Olaparib has been reported have promising effects among BRCA mutated ovarian cancer patients. This study aimed to evaluate the cost-effectiveness of olaparib as a maintenance therapy for BRCA ovarian cancer in Malaysia.

    METHODS: We developed a four-state partitioned survival model which compared treatment with olaparib versus routine surveillance (RS) from a Malaysian healthcare perspective. Mature overall survival (OS) data from the SOLO-1 study were used and extrapolated using parametric models. Medication costs and healthcare resource usage costs were derived from local inputs and publications. Deterministic and probabilistic sensitivity analyses (PSA) were performed to explore uncertainties.

    RESULTS: In Malaysia, treating patients with olaparib was found to be more costly compared to RS, with an incremental cost of RM149,858 (USD 33,213). Patients treated with olaparib increased life years by 3.05 years and increased quality adjusted life years (QALY) by 2.76 (9.45 years vs 6.40 years; 7.62 vs 4.86 QALY). This translated to an incremental cost-effectiveness ratio (ICER) of RM 49,159 (USD10,895) per life year gained and RM54,357 (USD 12,047) per QALY gained, respectively. ICERs were most sensitive to time horizon of treatment, discount rate for outcomes, cost of treatment and health state costs, but was above the RM53,770/QALY threshold.

    CONCLUSION: The use of olaparib is currently not a cost-effective strategy compared to routine surveillance based upon the current price in Malaysia for people with ovarian cancer with BRCA mutation, despite the improvement in overall survival.

    Matched MeSH terms: Neoplasm Recurrence, Local/genetics
  5. Raghuram N, Hasegawa D, Nakashima K, Rahman S, Antoniou E, Skajaa T, et al.
    Blood Adv, 2023 Nov 14;7(21):6532-6539.
    PMID: 36735769 DOI: 10.1182/bloodadvances.2022009381
    Children with Down syndrome (DS) are at a significantly higher risk of developing acute myeloid leukemia, also termed myeloid leukemia associated with DS (ML-DS). In contrast to the highly favorable prognosis of primary ML-DS, the limited data that are available for children who relapse or who have refractory ML-DS (r/r ML-DS) suggest a dismal prognosis. There are few clinical trials and no standardized treatment approach for this population. We conducted a retrospective analysis of international study groups and pediatric oncology centers and identified 62 patients who received treatment with curative intent for r/r ML-DS between year 2000 to 2021. Median time from diagnosis to relapse was 6.8 (range, 1.1-45.5) months. Three-year event-free survival (EFS) and overall survival (OS) were 20.9 ± 5.3% and 22.1 ± 5.4%, respectively. Survival was associated with receipt of hematopoietic stem cell transplantation (HSCT) (hazard ratio [HR], 0.28), duration of first complete remission (CR1) (HR, 0.31 for > 12 months) and attainment of remission after relapse (HR, 4.03). Patients who achieved complete remission (CR) before HSCT, had an improved OS and EFS of 56.0 ± 11.8% and 50.5 ± 11.9%, respectively compared to those who underwent HSCT without CR (3-year OS and EFS of 10.0 ± 9.5%). Treatment failure after HSCT was predominantly because of disease recurrence (52%) followed by treatment-related mortality (10%). The prognosis of r/r ML-DS remains dismal even in the current treatment period and serve as a reference point for current prognostication and future interventional studies. Clinical trials aimed at improving the survival of patients with r/r ML-DS are needed.
    Matched MeSH terms: Recurrence
  6. Imon RR, Aktar S, Morshed N, Nur SM, Mahtarin R, Rahman FA, et al.
    Medicine (Baltimore), 2023 Nov 10;102(45):e35347.
    PMID: 37960765 DOI: 10.1097/MD.0000000000035347
    Glypican-3 (GPC3), a membrane-bound heparan sulfate proteoglycan, has long been found to be dysregulated in human lung adenocarcinomas (LUADs). Nevertheless, the function, mutational profile, epigenetic regulation, co-expression profile, and clinicopathological significance of the GPC3 gene in LUAD progression are not well understood. In this study, we analyzed cancer microarray datasets from publicly available databases using bioinformatics tools to elucidate the above parameters. We observed significant downregulation of GPC3 in LUAD tissues compared to their normal counterparts, and this downregulation was associated with shorter overall survival (OS) and relapse-free survival (RFS). Nevertheless, no significant differences in the methylation pattern of GPC3 were observed between LUAD and normal tissues, although lower promoter methylation was observed in male patients. GPC3 expression was also found to correlate significantly with infiltration of B cells, CD8+, CD4+, macrophages, neutrophils, and dendritic cells in LUAD. In addition, a total of 11 missense mutations were identified in LUAD patients, and ~1.4% to 2.2% of LUAD patients had copy number amplifications in GPC3. Seventeen genes, mainly involved in dopamine receptor-mediated signaling pathways, were frequently co-expressed with GPC3. We also found 11 TFs and 7 miRNAs interacting with GPC3 and contributing to disease progression. Finally, we identified 3 potential inhibitors of GPC3 in human LUAD, namely heparitin, gemcitabine and arbutin. In conclusion, GPC3 may play an important role in the development of LUAD and could serve as a promising biomarker in LUAD.
    Matched MeSH terms: Neoplasm Recurrence, Local/genetics
  7. Azman AA, Siok-Fong C, Rajab NF, Md Zin RR, Ahmad Daud NN, Mohamad Hanif EA
    Mol Biol Rep, 2023 Sep;50(9):7909-7917.
    PMID: 37442895 DOI: 10.1007/s11033-023-08661-5
    Triple negative breast cancer (TNBC) is the most aggressive intrinsic breast cancer subtype characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and low levels of human epidermal growth factor receptor 2 (HER2). The complex nature of TNBC has resulted in little therapeutic progress for the past several decades. The standard of care remains the FEC cocktail (5-fluorouracil (5-FU), epirubicin and cyclophosphamide). However, early relapse and metastasis in TNBC patients persists in causing dismal clinical outcomes. Due to complex heterogeneity features of TNBC, identifying the biomarker associated to the chemoresistance remains a challenge. The emergence of the long non-coding RNA (lncRNA) as a potential signature may have proven to be a new deterrent to diagnostic and treatment options. Previous studies unveiled the associations of lncRNA in the development of TNBCs whereby the aggressiveness and response to therapies may be associated by the abrogation of the molecular mechanism lncRNA. Terminal differentiation induced ncRNA (TINCR) is a lncRNA which have been linked with many cancers including TNBC. The expression and behavior of TINCR may exert unfavorable outcome in TNBCs. Nevertheless, the underlying molecular mechanism of TINCR in driving chemoresistance in TNBC is not well understood. This review will highlight the potential molecular mechanisms of TINCR in TNBC chemoresistance and how it can serve as a future potential prognostic and therapeutic target for a better treatment intervention.
    Matched MeSH terms: Neoplasm Recurrence, Local
  8. Ariffin H, Chiew EKH, Oh BLZ, Lee SHR, Lim EH, Kham SKY, et al.
    J Clin Oncol, 2023 Jul 10;41(20):3642-3651.
    PMID: 37276496 DOI: 10.1200/JCO.22.02347
    PURPOSE: To investigate whether, for children with favorable-risk B-cell precursor ALL (BCP-ALL), an anthracycline-free protocol is noninferior to a modified Berlin-Frankfurt-Muenster ALL-IC2002 protocol, which includes 120 mg/m2 of anthracyclines.

    PATIENTS AND METHODS: Three hundred sixty-nine children with favorable-risk BCP-ALL (age 1-9 years, no extramedullary disease, and no high-risk genetics) who cleared minimal residual disease (≤0.01%) at the end of remission induction were enrolled into Ma-Spore (MS) ALL trials. One hundred sixty-seven standard-risk (SR) patients (34% of Malaysia-Singapore ALL 2003 study [MS2003]) were treated with the MS2003-SR protocol and received 120 mg/m2 of anthracyclines during delayed intensification while 202 patients (42% of MS2010) received an anthracycline-free successor protocol. The primary outcome was a noninferiority margin of 1.15 in 6-year event-free survival (EFS) between the MS2003-SR and MS2010-SR cohorts.

    RESULTS: The 6-year EFS of MS2003-SR and MS2010-SR (anthracycline-free) cohorts was 95.2% ± 1.7% and 96.5% ± 1.5%, respectively (P = .46). The corresponding 6-year overall survival was 97.6% and 99.0% ± 0.7% (P = .81), respectively. The cumulative incidence of relapse was 3.6% and 2.6%, respectively (P = .42). After adjustment for race, sex, age, presenting WBC, day 8 prednisolone response, and favorable genetic subgroups, the hazard ratio for MS2010-SR EFS was 0.98 (95% CI, 0.84 to 1.14; P = .79), confirming noninferiority. Compared with MS2003-SR, MS2010-SR had significantly lower episodes of bacteremia (30% v 45.6%; P = .04) and intensive care unit admissions (1.5% v 9.5%; P = .004).

    CONCLUSION: In comparison with MS2003-SR, the anthracycline-free MS2010-SR protocol is not inferior and was less toxic as treatment for favorable-risk childhood BCP-ALL.

    Matched MeSH terms: Neoplasm Recurrence, Local/drug therapy
  9. Pagliuca S, Gurnari C, Hercus C, Hergalant S, Hong S, Dhuyser A, et al.
    Nat Commun, 2023 May 31;14(1):3153.
    PMID: 37258544 DOI: 10.1038/s41467-023-38113-4
    Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.
    Matched MeSH terms: Recurrence
  10. Mohd Isa MF, Mohamed Ashraf Md MAM, Yusof MR, Faiz N G, Siti Rahmah H I Merican SRHIM
    Urologiia, 2023 May.
    PMID: 37401716
    For the past two decades urethral stenting became more popular for treatment of urethral stricture. However, urethral stents still not widely used in view of good outcome from urethroplasty surgery. The MemokathTM stent is the most popular in this field. It is manufactured from a biocompatible alloy of nickel and titanium. Most of the studies have been limited to single stent insertion, and no studies done for double stents insertion. An 81-year-old man with history of multiple anterior urethral strictures since 2013. He underwent internal urethrotomy in the same year but failed and was on urinary catheter since then. The MemokathTM 044TW was the option due to patient has multiple comorbidities. The micturating cystourethrogram (MCUG) and ascending urethrogram showed multiple anterior urethral strictures. He underwent direct visual internal urethrotomy and two MemokathTM stents inserted in the whole length of urethral. However, one year after procedure, he had recurrent lower urinary tract symptoms and ultimately developed acute urinary retention (AUR). Patients stents were removed endoscopically. During endoscopic removal, he had encrustation of both stents that causing obstructive symptoms. He is under our follow-up with no recurrent urinary retention or urosepsis with satisfactory uroflowmetry. Stent encrustation is known to be a common late complication of urethral stents. Stent encrustation should be suspected if patient comes with obstructive symptoms. Endoscopic is shown to be the best method to detect the cause of obstructed stent.
    Matched MeSH terms: Recurrence
  11. Mahmud KA, Ghazali FNF, Zahari MNI, Halim HA, Khalid AK, Toh ST, et al.
    J Robot Surg, 2023 Apr;17(2):613-618.
    PMID: 36183030 DOI: 10.1007/s11701-022-01456-z
    Transoral robotic surgery is a minimally invasive surgical technique that recently debuted in Malaysia. However, there are concerns over its cost, practicality, and feasibility in local settings. Our study aims to evaluate the surgical outcomes of transoral robotic surgery and discuss its learning curves. The clinical records of all patients who underwent transoral robotic surgery in a university hospital were reviewed. 25 patients were identified with a mean age of 43.9 years. The commonest indication was obstructive sleep apnoea (OSA) (76%), followed by base of tongue carcinoma (16%), recurrent tonsilitis and Wharton's duct cyst (4% each). For excision of tongue base in obstructive sleep apnoea without epiglottectomy, the mean operating time was 2.3(±0.9) hours with an average of 2.8(±0.4) days of hospital stay. The success rate for OSA surgery was seen in 78.9% of cases. The mean operating time for transoral excision of tongue base carcinoma was 4.3(±2.5) hours, whereas the mean hospital stay was 9(±3.6) days. All surgical margins were cleared with no recurrence except for one patient. The recurrent tumour was successfully excised via transoral robotic surgery, and he remained disease free after one year. The most frequent post-operative complaints were dysphagia, post-nasal drip, and hypogeusia. Transoral robotic surgery in Malaysia is in the commencement phase, where some pitfalls are expected. Opportunities should be given for more surgeons to acquire this technique so that minimally invasive surgery for head and neck diseases is readily available for patients in middle-income countries.
    Matched MeSH terms: Neoplasm Recurrence, Local
  12. Zucchelli G, Chun KRJ, Khelae SK, Földesi C, Kueffer FJ, van Bragt KA, et al.
    J Interv Card Electrophysiol, 2023 Apr;66(3):711-722.
    PMID: 36331681 DOI: 10.1007/s10840-022-01388-6
    BACKGROUND: Cryoballoon ablation (CBA) is an effective first-line treatment for symptomatic atrial fibrillation (AF), as recently demonstrated by three randomized trials. This sub-analysis of the Cryo Global Registry aims to examine current clinical practices of first-line CBA.

    METHODS: AF patients treated with first-line CBA were compared to CBA in antiarrhythmic drug (AAD)-refractory patients at 12 months. Efficacy was examined using time-to-first atrial arrhythmia recurrence following a 90-day blanking period. Healthcare utilization was evaluated by repeat ablations and hospitalizations. Disease burden was examined by assessing quality of life (QOL) and patients' reporting of symptoms.

    RESULTS: Of 1394 patients, 433 (31.1%) were treated with first-line CBA, which was more frequent in high-volume centers. Serious procedure-related adverse event rates were similar. Efficacy at 12 months was higher in the first-line group (87.8 vs. 81.6%, HRunadj 0.64 (95% CI 0.47-0.88); p 

    Matched MeSH terms: Recurrence
  13. Erker C, Mynarek M, Bailey S, Mazewski CM, Baroni L, Massimino M, et al.
    J Clin Oncol, 2023 Apr 01;41(10):1921-1932.
    PMID: 36548930 DOI: 10.1200/JCO.21.02968
    PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy.

    METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors.

    RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007).

    CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

    Matched MeSH terms: Neoplasm Recurrence, Local
  14. Feng J, Xi Z, Jiang X, Li Y, Nik Nabil WN, Liu M, et al.
    Cancer Lett, 2023 Feb 01;554:216011.
    PMID: 36442771 DOI: 10.1016/j.canlet.2022.216011
    Quiescent cancer cells (QCCs), also known as dormant cancer cells, resist and survive chemo- and radiotherapy, resulting in treatment failure and later cancer recurrence when QCCs resume cell cycle progression. However, drugs selectively targeting QCCs are lacking. Saikosaponin A (SSA) derived from Bupleurum DC., is highly potent in eradicating multidrug-resistant prostate QCCs compared with proliferative prostate cancer cells. By further exacerbating the already increased autophagy through inactivation of Akt-mTOR signaling, SSA triggered cell death in QCCs. Contrarily, inhibition of autophagy or activation of Akt signaling pathway prevented SSA-induced cell death. The multicycle of Docetaxel treatments increased the proportion of QCCs, whereas administering SSA at intervals of Docetaxel treatments aggravated cell death in vitro and led to tumor growth arrest and cell death in vivo. In conclusion, SSA is posed as a novel QCCs-eradicating agent by aggravating autophagy in QCCs. In combination with the current therapy, SSA has potential to improve treatment effectiveness and to prevent cancer recurrence.
    Matched MeSH terms: Neoplasm Recurrence, Local
  15. Harrington KJ, Burtness B, Greil R, Soulières D, Tahara M, de Castro G, et al.
    J Clin Oncol, 2023 Feb 01;41(4):790-802.
    PMID: 36219809 DOI: 10.1200/JCO.21.02508
    PURPOSE: Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented.

    METHODS: Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment.

    RESULTS: The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes.

    CONCLUSION: With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.

    Matched MeSH terms: Neoplasm Recurrence, Local/drug therapy; Neoplasm Recurrence, Local/etiology
  16. Pagano R, Salamian A, Zielinski J, Beroun A, Nalberczak-Skóra M, Skonieczna E, et al.
    Mol Psychiatry, 2023 Feb;28(2):733-745.
    PMID: 36357670 DOI: 10.1038/s41380-022-01849-4
    Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of the AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (Arc)/ARG3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol cue exposure may thus be a selective new mechanism for relapse prevention.
    Matched MeSH terms: Recurrence
  17. Tippett VL, Tattersall L, Ab Latif NB, Shah KM, Lawson MA, Gartland A
    Oncogene, 2023 Jan;42(4):259-277.
    PMID: 36434179 DOI: 10.1038/s41388-022-02529-x
    Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate, adriamycin (doxorubicin) and platinum (cisplatin). Due to the rarity of OS, the generation of relevant cell models as tools for drug discovery is paramount to tackling this issue. Four literature databases were systematically searched using pre-determined search terms to identify MAP resistant OS cell lines and patients. Drug exposure strategies used to develop cell models of resistance and the impact of these on the differential expression of resistance associated genes, proteins and non-coding RNAs are reported. A comparison to clinical studies in relation to chemotherapy response, relapse and metastasis was then made. The search retrieved 1891 papers of which 52 were relevant. Commonly, cell lines were derived from Caucasian patients with epithelial or fibroblastic subtypes. The strategy for model development varied with most opting for continuous over pulsed chemotherapy exposure. A diverse resistance level was observed between models (2.2-338 fold) with 63% of models exceeding clinically reported resistance levels which may affect the expression of chemoresistance factors. In vitro p-glycoprotein overexpression is a key resistance mechanism; however, from the available literature to date this does not translate to innate resistance in patients. The selection of models with a lower fold resistance may better reflect the clinical situation. A comparison of standardised strategies in models and variants should be performed to determine their impact on resistance markers. Clinical studies are required to determine the impact of resistance markers identified in vitro in poor responders to MAP treatment, specifically with respect to innate and acquired resistance. A shift from seeking disputed and undruggable mechanisms to clinically relevant resistance mechanisms may identify key resistance markers that can be targeted for patient benefit after a 40-year wait.
    Matched MeSH terms: Neoplasm Recurrence, Local/drug therapy
  18. Ong ZM, Arip M, Ching YM, Kumar L, Terumalay S, Sim SH, et al.
    Mult Scler Relat Disord, 2022 Nov;67:104168.
    PMID: 36274473 DOI: 10.1016/j.msard.2022.104168
    INTRODUCTION: CNS IIDDs1 tested positive for anti-MOG2 are known to have a distinct clinical profile with a better overall prognosis.

    OBJECTIVES: We aim to determine the prevalence, demographic and clinical characteristics of MOG antibody disease (MOGAD) specifically identifying any ethnic variations unique to our local population, with global perspectives.

    METHODS: This is a cross-sectional study conducted at the Neurology Department, Kuala Lumpur Hospital from January 2018 to January 2021. Out of 750 CNS IIDDs, seventy-eight consecutive anti-AQP4 antibody negative NMOSD/high risk undifferentiated relapsing or monophasic CNSIIDD subjects were tested for anti-MOG.

    RESULTS: Anti-MOG was positive in thirty six out of seventy-eight (%)(46.1%) seronegative patients. The prevalence of MOGAD in our Malaysian population is 0.12 per 100,000 persons with less marked female preponderance of 2:1 and younger age at onset of 23.8 ± 14.4 years. Despite a predominantly ethnic Malay population, a high proportion of our MOGAD patients were Indian (Proportion of Malay:Chinese:Indian:others; 16:9:10:1, prevalence 0.5 per 100,000 population for Indians) with favourable disease course in the most with minor exceptions. Monophasic and relapsing disease course was seen in 11.2% and 88.8% of patients respectively. However, fulminant aggressive disease can occur especially amongst the Chinese and paediatric cohorts. Optic neuritis, NMOSD and ADEM were the commonest presentations at onset and first relapse. EDSS at diagnosis, first relapse, and last follow-up were 4.5±2.5, 3±2.0, and 1.75(range 1-3). Neuroimaging showed large, fluffy, PRES- like supratentorial cortical, periventricular deep white matter ,diencephalon lesions,enhancing anterior optic nerve with or without chiasmal sparring lesions and cervical/cervicothoracic involvement. Area post rema lesions were rare. Threshold steroid levels exist relapsing on withdrawal some fulminantly requiring Immunosuppressants(rituximab) and intravenous immunoglobulins to maintain remission.

    CONCLUSION: Malaysian MOGAD profile was similar to its international descriptions of the disease with ethnic selectivity for Indians. Prolonged steroid maintenance is essential to prevent relapses. Fulminant aggressive cases of MOGAD especially amongst Paediatric patients and the Chinese cohort have been reported.

    Matched MeSH terms: Recurrence
  19. Dzul Keflee R, Leong KH, Ogawa S, Bignon J, Chan MC, Kong KW
    Biochem Pharmacol, 2022 Nov;205:115262.
    PMID: 36191627 DOI: 10.1016/j.bcp.2022.115262
    The role of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) has been vastly studied over the last decade. This has led to the rapid development of many generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, patients treated with third-generation TKIs (osimertinib, avitinib and rociletinib) targeting the EGFR T790M mutation have shown emerging resistances and relapses. Therefore, further molecular understanding of NSCLC mutations, bypass signalling, tumour microenvironment and the existence of cancer stem cells to overcome such resistances is warranted. This will pave the way for designing novel and effective chemotherapies to improve patients' overall survival. In this review, we provide an overview of the multifaceted mechanisms of resistance towards EGFR-TKIs, as well as the challenges and perspectives that should be addressed in strategising chemotherapeutic treatments to overcome the ever-evolving and adaptive nature of NSCLC.
    Matched MeSH terms: Neoplasm Recurrence, Local/chemically induced; Neoplasm Recurrence, Local/drug therapy
  20. Lai PS, Usama SM, Kiew LV, Lee HB, Chung LY, Burgess K, et al.
    Cancer Immunol Immunother, 2022 Sep;71(9):2099-2108.
    PMID: 35032175 DOI: 10.1007/s00262-022-03147-y
    Conventional cancer therapies such as chemotherapy are non-selective and induce immune system anergy, which lead to serious side effects and tumor relapse. It is a challenge to prime the body's immune system in the cancer-bearing subject to produce cancer antigen-targeting antibodies, as most tumor-associated antigens are expressed abundantly in cancer cells and some of normal cells. This study illustrates how hapten-based pre-immunization (for anti-hapten antibodies production) combined with cancer receptor labeling with hapten antigen constructs can elicit antibody-dependent cellular phagocytosis (ADCP). Thus, the hapten antigen 2,4-dinitrophenol (DNP) was covalently combined with a cancer receptor-binding dipeptide (IYIY) to form a dipeptide-hapten construct (IYIY-DNP, MW = 1322.33) that targets the tropomyosin receptor kinase C (TrkC)-expressed on the surface of metastatic cancer cells. IYIY-DNP facilitated selective association of RAW264.7 macrophages to the TrkC expressing 4T1 cancer cells in vitro, forming cell aggregates in the presence of anti-DNP antibodies, suggesting initiation of anti-DNP antibody-dependent cancer cell recognition of macrophages by the IYIY-DNP. In in vivo, IYIY-DNP at 10 mg/kg suppressed growth of 4T1 tumors in DNP-immunized BALB/c mice by 45% (p 
    Matched MeSH terms: Neoplasm Recurrence, Local*
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